Fexofenadine, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α-α-dimethylphenylacetic acid, formerly known as terfenadine carboxylic acid metabolite, is a potent non-sedating antihistamine sold by Aventis in the United States under the tradename ALLEGRA® and elsewhere in the world under the tradename TELFAST®.
The importance of commercially viable syntheses of fexofenadine is attested to by the scores of patents to fexofenadine processes. Piperidine derivatives related to fexofenadine are disclosed in the following U.S. Pat. Nos. 4,254,129; 4,254,130; 4,285,957; and 4,285,958. In these patents, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid and related compounds are prepared by alkylation of a substituted piperidine derivative of the formula:
with an ω-haloalkyl substituted phenyl ketone of the formula:
wherein the substituents halo, R1, R2, n, Z, and R6 are described in column 6 of U.S. Pat. No. 4,254,130.
U.S. Pat. No. 4,254,130 indicates that ω-haloalkyl substituted phenyl ketones, wherein Z is hydrogen, are prepared by reacting an appropriate straight or branched lower alkyl C1-6 ester of α-α-dimethylphenylacetic acid with a compound of the following formula:
under the general conditions of a Friedel-Crafts acylation, wherein halo and m are described in column 11 of U.S. Pat. No. 4,254,129. The reaction is carried out in carbon disulfide as the preferred solvent.
A more recent approach via Friedel-Crafts acylation with succinic anhydride, condensation with the piperidine and reduction of the ketone and amide carbonyls has issued as U.S. Pat. No. 6,743,941.
It has been found that the Friedel-Crafts methods have two significant shortcomings: (1) only acyl halides or anhydrides can be used; (2) in the particular case of the fexofenadine intermediate phenyl ketones, a higher regioselectivity of the Friedel-Crafts acylation would be desirable.
In another approach, which is the subject of a series of patents to D'Ambra and others (U.S. Pat. Nos. 5,589,487; 6,153,754 and 6,201,124), fexofenadine is synthesized by a regioselective method employing non-Friedel-Crafts acylation. The processes of the D'Ambra patents involve acylation of an aromatic ring at a position already para-substituted with a reactive species. Acylation can be carried out by a variety of techniques, including a butyl derivative acylating agent, a 4-(α,α-disubstituted)-toluic acid derivative acylating agent, or an organometallic coupling reaction. Since such procedures do not involve replacement of hydrogen on an aromatic ring, they are distinguished from electrophilic aromatic substitutions like the Friedel-Crafts acylation reaction.
Other procedures for producing fexofenadine are disclosed in PCT Application Nos. WO95/00482, WO94/03170, and WO95/00480. A more recent approach is outlined in US published application 2003/0166682, in which an intermediate nitrile is hydrolyzed to fexofenadine.
The present invention is directed toward an improved process for preparation of fexofenadine.